The present invention provides a novel stimulatory device for the controlled production of angiogenic growth factors. More specifically, the present invention provides a subthreshold pulse generator for the local production of vascular endothelial growth factor.
Coronary artery disease (CAD) results from arteriosclerosis of blood vessels serving the heart. Arteriosclerosis is a hardening and narrowing of the arteries. Often the arteries of the heart can suddenly become so severely blocked that there is inadequate blood supply to areas of the heart, leading to the occurrence of a myocardial infarction. The area of damage where the reduced blood flow has occurred is called the ischemic area. The ischemic area of the heart, because it does not get adequate blood flow, is starved of oxygen and nutrients. This blockage, if not treated quickly, can lead to severe tissue damage. Often surgical procedures are used to graft new blood vessels to the ischemic area to improve circulation. Alternatively, angioplasty or stenting of the blocked blood vessel is done to reopen or maintain blood flow. However, by-passing or reopening of the arteries is often not possible because of limitations of present methodologies and the risk to the patient from surgical intervention.
Damage from ischemia from insufficient blood circulation can also occur in blood vessels peripheral to the heart. Peripheral arterial occlusive disease (PAOD), caused by arteriosclerosis or by formation of vascular blood clots from diseases such as diabetes, often leads to loss of external limbs.
One way to address the need for improved blood flow to ischemic tissue is to generate new blood vessels. Angiogenic factors are known to directly participate in the formation of new blood vessels. Local administration of recombinant angiogenic growth factors, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), can salvage ischemic areas of myocardial and skeletal muscle tissue in animal models. A number of approaches have been developed to deliver these factors to ischemic areas in hope of developing new blood vessels, including direct injection, electroporation, and delivery using retroviral vectors.
The direct injection of angiogenic growth factors has many problems associated with it, most notably problems with effective delivery of the factors into the cells. Electroporation is a possible method of delivery of genetic materials encoding angiogenic factors; however, the transfection efficiency is still very low and the high-energy pulses directed to the tissue often kill many healthy cells. Alternatively, others have sought to develop viral based gene delivery systems to directly produce angiogenic factors in vivo; however, this approach requires considerably more development before it is considered to be a safe and effective therapy. Although extensive research continues in the areas of gene delivery, very little has been reported on methods to control and regulate gene expression in vivo. The inability to effectively deliver the agent to the target tissue, therefore, is one of the major limitations of the use of such agents. During delivery of the angiogenic factors the effectiveness is often destroyed or lost.
Recent work has been published related to using electrical fields to stimulate natural production of angiogenic growth factors. WO 00/27466 describes use of constant voltage sources to generate electrical fields for stimulating angiogenesis. The described voltages are on the order of 50-300 volts/cm, which would also stimulate contractile responses during stimulation. Stimulation of angiogenesis without causing a contractile muscle response would be advantageous. In a recent publication (Circulation, 1999;99:2682-2687) it was reported that low-voltage electrical stimulation of skeletal muscle induced de novo synthesis of VEGF protein and promoted angiogenesis. Further work is needed in this research area. Even with the known methods in the art, there still exists a need for additional and more effective subthreshold devices and more efficient methods for the controlled delivery of angiogenic growth factors to promote angiogenesis in muscle tissue, and methodologies that can be used to stimulate angiogenesis in cardiac and vascular tissue.
The present invention addresses a number of problems existing in the prior art with respect to controlled local delivery of angiogenic factors. Various embodiments of the present invention provide solutions and to one or more of the problems existing in the prior art with respect to delivery of angiogenic factors. The present invention provides a novel electrical pulse generator for angiogenesis and production angiogenic growth factors.
The present invention provides an electrical pulse generator for providing subthreshold pulses. The present device can be adapted to a range of subthreshold pulses by modulating the time, frequency, and delivery of a given stimulus. The present generator allows the use of a constant voltage, regardless of the distance between electrodes by allowing a variable field density. The present generator allows for control over the amplitude of the voltage and for charge balancing of the delivered and recovered charged pulse.
In another embodiment, the subthreshold pulse generator can be used externally, but preferably is designed and configured to be implantable. The subthreshold pulse generator includes a power supply and a control mechanism interconnected with the power supply. Optionally, the pulse generator can be used with a plurality of electrodes in electrical communication with the power supply. The present generator is also capable of checking the lead continuity at a predesignated time.
The invention also provides a subthreshold pulse generator for a patient in need thereof. In one aspect, the invention includes a method for reducing or repairing tissue injury or disease by providing a means for regulating angiogenic growth factor production. In another aspect the subthreshold stimulation provided is sufficient to stimulate angiogenesis in the targeted body tissue. In yet another aspect, the present invention provides a novel method of pacing that is capable of stimulating cells or tissues for the controlled expression of angiogenic factors.
These and other objects and features of the invention will become more fully apparent when the following detailed description is read in conjunction with the accompanying drawings.